Rate of Correction and All-Cause Mortality in Patients With Severe Hypernatremia

Key Points Question Is the rate of correction associated with mortality in patients with severe hypernatremia? Findings In this cohort study of 4265 adults with severe hypernatremia, patient survival was strongly correlated with hypernatremia correction rate. There was no evidence of any neurological complications associated with rapid correction of severe hypernatremia. Meaning The results suggest that faster correction rates than currently recommended for severe hypernatremia might translate to better patient outcomes.


Introduction
Hypernatremia is a common finding in hospitalized patients, with reported incidence 1% to 3%, 1 and up to 9% in intensive care units (ICUs). 2 Hypernatremia indicates a deficit in total body water, usually occurring in patients with inadequate access to water or impaired thirst mechanisms such as ICU patients, infants, and older adults. 3The clinical presentation of hypernatremia ranges from mild, nonspecific symptoms such as nausea, headache, and lethargy, to severe neurological symptoms such as seizure and coma. 4Hypernatremia is associated with higher mortality rates than any other electrolyte abnormality, although this is often attributed to the comorbidities of patients with hypernatremia rather than its direct consequences. 4ta regarding the optimal rate of correction of hypernatremia are lacking.6][7][8] These complications were documented mainly in neonates. 9,10Clinical data supporting the safety and clinical benefits of slow correction of hypernatremia in adults are scarce.Several small studies reported that slow correction of hypernatremia is associated with excess mortality. 7,11Faster correction rates of up to 1 millimole per liter per hour have been suggested as appropriate for patients with rapidly developing hypernatremia. 6,8A recent study found no association between rate of correction of hypernatremia and clinical outcomes. 5Whether current guidelines reflect the optimal balance between patient safety and potential harm is unknown.
The current study aimed to elucidate the association between the rate of correction of hypernatremia and patient outcomes.We hypothesized that fast correction rates would be associated with more favorable patient outcomes.

Methods
This retrospective cohort study was approved by the Tel Aviv Sourasky Medical Center institutional review board (IRB).Informed consent was waived by the IRB according to local policy for anonymized retrospective studies.We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. 14

Study Population
The study cohort included all adult patients (aged Ն18 years) admitted between June 2007 and November 2021 to the Tel Aviv Sourasky Medical Center, a tertiary university-affiliated acute care hospital, who had severe hypernatremia (serum sodium Ն155mmol/L [to convert to mEq/L, multiply by 1.0]). 2 Patients with severe hypernatremia at admission were categorized as admission hypernatremia, and those who developed severe hypernatremia during the hospitalization were categorized as hospital-acquired hypernatremia, consistent with previous studies. 5For patients with several episodes of hypernatremia during the study period, only the first episode was included in the present study.We excluded patients with no serum sodium values following documentation of severe hypernatremia and patients on dialysis.Patients with initial blood sodium concentrations exceeding a prespecified threshold of 190 mmol/L as well as those with the 0.05% highest and lowest sodium correction rates between 2 consecutive measurements were also excluded from the final study cohort to avoid outliers stemming from measurement errors of blood sodium levels.

Data Source, Measurements, and Variables
Data were obtained using MDClone, a query tool that provides comprehensive patient-level data of wide-ranging variables in a defined timeframe around an index event. 12Extracted data included age, gender, comorbidities included in the Charlson comorbidity index, 13 and up to 10 consecutive serum sodium measurements following the first documentation of severe hypernatremia.Serum glucose, magnesium, potassium, creatinine, blood urea nitrogen (BUN), bicarbonate, albumin, calcium, and

JAMA Network Open | Nephrology
Rate of Correction and All-Cause Mortality in Patients With Severe Hypernatremia phosphorous concomitant with severe hypernatremia were also extracted.We also collected data regarding diuretic medications potentially related to dehydration, including furosemide, thiazide and thiazide-like diuretics, aldosterone antagonists, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors.Vital status was ascertained through the patient's health maintenance organization.
In order to identify potential central nervous system complications of an overly rapid correction of severe hypernatremia, we searched for diagnoses of cerebral edema (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 348.5), altered mental status (ICD-9-CM code 780), seizures (ICD-9-CM code 780.39), or epilepsy (ICD-9-CM code 345.9).The electronic health records of all patients with 1 of these diagnoses were examined by 1 of the authors (E.F.) to ascertain the associations between hypernatremia and central nervous system complications.Complications were deemed related to hypernatremia if the association was clinically plausible to the treating physicians or if no other reasonable explanation was present upon examination of the patient's medical record by the investigators.

Correction Rate Calculation and Definitions
For each patient the initial sodium level was considered as the first sodium measurement equal to or exceeding 155 mmol/L.The subsequent 10 consecutive sodium measurements were recorded.The mean correction rate between documentation of severe hypernatremia and the first documented eunatremia (sodium Յ145mmol/L) was calculated for all patients.For patients with no documentation of eunatremia, the mean correction rate up to the last documented sodium level or the 10th sodium measurement following the documentation of severe hypernatremia was calculated.Fast correction rates were defined as those exceeding 0.5 mmol/L/h, while patients with correction rates less than or equal to 0.5 mmol/L/h were grouped as having slow correction rates.
The maximal sodium correction rate was calculated for each patient, defined as the fastest correction rate between any 2 consecutive sodium measurements.The sodium correction within the first 24 hours following documentation of hypernatremia was also calculated for each patient using the latest sodium measurement within the first 24 hours from hypernatremia documentation.

Study End Points
The primary outcome was all-cause mortality within 30 days.Secondary outcomes were defined as mortality within 7 days and 365 days, length of hospitalization, and rate of neurological complications.

Statistical Analysis
Patients with fast correction rates were compared with patients with slow correction rates for the entire cohort and stratified by admission hypernatremia vs hospital-acquired hypernatremia.Absolute values of sodium correction for the first 24 hours following documentation of severe hypernatremia were also compared between both groups according to prespecified cutoffs of 8, 10, and 12 mmol/L/d.Categorical variables were compared using the Fischer exact test, and continuous variables were compared using the Wilcoxon rank-sum test.Kaplan-Meier survival curves were compared using the MaxCombo test with the following sets of Flemming-Harrington weights ([0,0], 15 Logistic regression was used to determine the association between hypernatremia correction rates and mortality and expressed as the odds ratio (OR).The regression was conducted both with and without adjusting for clinically relevant variables, including demographics (age, gender), Charlson comorbidity index, initial sodium, potassium, and creatinine levels, hospitalization in an ICU, and severe hyperglycemia (defined as glucose levels exceeding 500 mmol/L).Only patients with full data for all of the controlled covariates were included in the adjusted OR (aOR) analysis.Correlation between sodium correction within the first 24 hours and mortality was calculated using the Pearson correlation coefficient.A P value of .05 was considered statistically significant for all comparisons.To correct for multiple comparisons, we set for each group of results an adjusted significance threshold based on the Bonferroni correction such that P for adjustment <.05 / (number of comparisons).The analysis was conducted using Python version 3.9 (Python Software Foundation).The MaxCombo test was run using the nph library in R version 4.2.1.
Statistical analysis was performed from April 2022 to August 2023.

Discussion
Despite the high prevalence of hypernatremia, data guiding optimal correction rates are scarce.To our knowledge, we report on the largest cohort to date of patients with severe hypernatremia.Rapid correction rate of hypernatremia was associated with better overall survival and shorter hospitalizations.We did not identify any evidence supporting an association between rapid rate of correction and patient harm, and no neurological complications were observed in patients with rapid correction.These findings challenge current expert opinion advising slower, controlled correction rates to avoid potentially devastating neurological complications.
Most previous studies of patients with hypernatremia included less than 200 patients. 7,11aller studies are subject to potentially fragile results leading to coincidental findings, selection bias, and publication bias. 16To our knowledge, the largest study to date, including 450 patients, reported no association between hypernatremia correction rate and patient survival. 5However, these were patients who were critically ill and hospitalized in ICUs, representing a different patient population.Furthermore, we reported on a considerably larger cohort of patients, making the results more robust.
The currently suggested correction rate of hypernatremia is an extrapolation of the suggested correction rate in neonates, a very different patient population with different physiology, comorbidities, and etiologies for hypernatremia.Faster correction of hypernatremia in adults can theoretically improve patient outcomes in several ways.Faster correction of severe volume contraction and the accompanying acute kidney failure can reduce the risk of potential adverse events, such as electrolyte abnormalities, infections, chronic kidney failure, and cardiovascular complications. 17Longer hospitalizations associated with slower correction of hypernatremia are also associated with potential complications such as hospital-acquired infections, falls, delirium and deconditioning, more so in patients with kidney failure, all known to be associated with worse patient outcomes. 18Additionally, it is possible that hypernatremia directly causes time-dependent neurological injury, which can be minimized with rapid correction. 19This hypothesis, supported by the reported results, should be tested separately, perhaps in an animal model.Some of the rationale supporting current expert opinion recommending controlled correction of hypernatremia rests on a perceived symmetry with correction of hyponatremia. 20While it is appealing to group these 2 common sodium disorders together, published data do not support this approach.The evidence supporting slow correction of hyponatremia is supported by animal studies, numerous case reports and large observational studies. 21In contrast, there are no convincing reports of even 1 adult harmed by rapid correction of hypernatremia.From a physiological perspective the risk of neurological complications seems to be much higher with rapid correction of hyponatremia, as the adaptations of brain cells to hypernatremia are much slower than to hyponatremia. 20Also, while the risk of complication associated with rapid correction is more common with chronic hyponatremia compared with acute hyponatremia, chronic hypernatremia is considerably less common than acute hypernatremia.Our results were comparable for patients with hypernatremia on admission compared with those who were diagnosed during hospitalization, also supporting the safety of rapid correction of hypernatremia even when there is no clear documentation of an acute condition.
The 30-day mortality was alarmingly high in the reported cohort.This is in line with previous studies of severe hypernatremia. 5,7,11The absolute difference in survival between rapidly and slowly corrected patients was very large and remained so after adjustment for potential confounders.
Interestingly, the size of the absolute difference in survival was comparable at 30 days and at 1 year following documentation of severe hypernatremia.This might suggest that the different mortality rates do not represent differences in the patient populations unaccounted by the statistical analysis, but rather the results of the treatment strategies for severe hypernatremia, namely the rate of correction.An additional support to this hypothesis is the strong correlation reported between the absolute sodium correction in the first 24 hours and patient survival.This implies that the high

Limitations
This study has several important limitations.First, the retrospective nature of the study increases the risk for bias and confounding.Fast correction of hypernatremia might be a marker of healthier patients, and not directly associated with survival.This seems less likely as results remained statistically significant after adjusting for comorbidities, and as there was no excess mortality in the slow correction rate group between 30 days and 1 year, implying differences in mortality rates are less likely to be attributed to comorbidities and background factors.Unaccounted confounding factors and data entry mistakes might affect the reported results.The substantial discrepancy in sample sizes between the slow and fast correction rate groups, representing class imbalance, might also affect the reported results.Second, many patients were corrected slower than possible under the current guidelines, perhaps due to concerns of overly rapid correction.Of note, the median maximal correction rates in the slow correction rate group are close to currently suggested correction rates for these patients, probably reflecting relatively aggressive initiation of rehydration followed by slower and more careful treatment.Moreover, this slow rate of correction of hypernatremia is similar to rates reported in previous non-ICU studies, 11 implying slow correction rates might be more common than previously thought and perhaps representing physician concerns of neurological complications of overcorrection.It is possible that faster rates of correction might have translated to better patient outcomes.Third, the study did not include different treatments for hypernatremia, which could potentially influence prognosis.Fourth, our analysis did not include correction of sodium levels for hyperglycemia.However, this is probably not a significant factor for most patients and should be comparable between the 2 studied groups.Also, for the fast correction group, any hyperglycemia would have made true correction rates even higher than currently calculated, underlining the safety of rapid correction.Fifth, our results might not be generalizable to patients with less severe hypernatremia, or for patients in other hospitals.Strengths of our study include the large sample size and the inclusion of all consecutive patients with severe hypernatremia in a predefined time frame.

Conclusion
In perhaps the largest patient cohort published to date, faster correction of severe hypernatremia than currently suggested was associated with significantly better survival rates.Even very fast correction rates were not associated with adverse neurological events.Health care professionals caring for patients with hypernatremia should take these findings into account when considering the optimal correction rates for their patients.

Figure 1 .
Figure 1.Thirty-Day Survival Curves for Patients With Fast and Slow Sodium Correction Rates

Figure 2 .Figure 3 .
Figure 2. Thirty-Day Mortality According to First 24 Hours Sodium Correction

Table 2 .
Sodium Levels, Correction Rates, and Correction Durations in Patients With Slow vs Fast Sodium Correction Rates SI conversion rate: To convert sodium to mEq/L, multiply by 1.0.

JAMA Network Open | Nephrology Rate
of Correction and All-Cause Mortality in Patients With Severe Hypernatremia There were 3321 patients (77.9%) who had hospital-acquired hypernatremia, and 994 (22.1%) had hypernatremia on admission (eTable 2 in Supplement 1).Patients with hypernatremia on admission were older than those with hypernatremia during hospitalization, with a median (IQR) age of 85 (74-90) years vs 76 (62-85) years (eTable 2 in Supplement 1).They also tended to have more comorbidities (median [IQR] Charlson comorbidity index of 5[4-6]points vs 4[3-6]points; P < .001).There were 12 patients with coded diagnoses of neurological complications: 6 patients with seizures, 5 with changes in consciousness, and 1 with cerebral edema.In all 12 cases, neurological complications were diagnosed and coded prior to initiation of correction of hypernatremia.All 12 cases were in the slow correction rate group.No neurological complications were attributed to rapid rate of correction of hypernatremia by the treating physicians or by the investigators.

JAMA Network Open | Nephrology Rate
of Correction and All-Cause Mortality in Patients With Severe Hypernatremia mortality rates known to be associated with severe hypernatremia might be partly attributed to lack of aggressive rehydration, which might improve patient outcomes.